Talazoparib Approved in Europe for BRCA-Mutant Breast Cancer

Andreas Penk, MD

The European Commission has approved single-agent talazoparib (Talzenna) for the treatment of adult patients with germline BRCA1/2-mutant, HER2-negative locally advanced or metastatic breast cancer.¹

The approval is based on findings from the phase III EMBRACA study, in which talazoparib led to a 46% reduction in the risk of disease progression a median compared with standard chemotherapy in patients with germline BRCA1/2-mutant, HER2-negative locally advanced or metastatic breast cancer.²

“Today’s approval of Talzenna for certain patients with advanced-stage breast cancer and an inherited BRCA mutation is the latest example of our successful precision medicine approach to drug development,” Andreas Penk, MD, regional president, Oncology International Developed Markets at Pfizer, the developer of talazoparib, stated in a press release. “This important milestone builds on Pfizer’s decades-long legacy of developing therapies that improve outcomes for patients with breast cancer. We are thrilled that we can now offer these patients in Europe, who are often diagnosed at a younger age and have limited treatment options, an effective, once-daily, alternative treatment to chemotherapy.”

In order to receive the PARP inhibitor, patients must have been previously treated with an anthracycline and/or a taxane in the (neo)adjuvant, locally advanced, or metastatic setting unless they were determined to be ineligible for such therapies. For patients with hormone receptor—positive breast cancer, they should have received prior treatment with an endocrine-based therapy or be considered not unsuitable to have it.

In the international, open-label, phase III EMBRACA study, 431 patients with germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer were randomized 2:1 to receive 1 mg daily of oral talazoparib (n = 287) or physician’s choice of chemotherapy (n = 144), which included capecitabine (received by 44% of patients), eribulin (40%), gemcitabine (10%), and vinorelbine (7%).

To be eligible for enrollment, patients must have received ≤3 prior cytotoxic chemotherapy regimens for locally advanced or metastatic disease. Moreover, patients must have received treatment with an anthracycline and/or a taxane, unless contraindicated, in the neoadjuvant, adjuvant, and/or metastatic setting. The primary endpoint was progression-free survival (PFS), as assessed by blinded independent central review, and secondary endpoints were overall survival (OS), safety, and overall response rate (ORR).

Baseline characteristics were mostly well balanced between the 2 arms. However, in the talazoparib arm, 63.4% of patients were aged <50 years versus 46.5% of patients in the control arm. Fifteen percent of patients on talazoparib had a history of central nervous system metastasis versus 13.9% in the chemotherapy arm. In the talazoparib group, 37.6% of patients had a disease-free interval—from their initial diagnosis to advanced breast cancer—of under 12 months versus 29.2% with chemotherapy.

At a median follow-up of 11.2 months, data showed that the median PFS was 8.6 months (95% CI, 7.2-9.3) with talazoparib and 5.6 months (95% CI, 4.2-6.7) with chemotherapy, respectively (HR, 0.54; 95% CI, 0.41-0.71; P <.0001). Moreover, the ORRs were 62.6% (95% CI, 55.8-69.0) with talazoparib and 27.2% (95% CI, 19.3-36.3) with chemotherapy (odds ratio, 4.99; 95% CI, 2.9-8.8; 2-sided P value <.0001). The PFS benefit with talazoparib was seen across all predetermined patient subgroups.

The median duration of treatment was 6.1 months compared with 3.9 months for talazoparib and chemotherapy, respectively. Among patients with measurable disease, the complete response rate with talazoparib was 5.5%, the partial response rate was 57.1%, and the stable disease rate was 21.0%. The corresponding rates in the physician’s choice arm were 0%, 27.2%, and 31.6%, respectively.

Additional results showed that the median duration of response was 5.4 months (95% CI, 4.2-6.3) with talazoparib and 3.1 months (95% CI, 2.8-5.6) with chemotherapy (HR, 0.43; 95% CI, 0.27-0.70; P = .0005). Moreover, the 1-year probability of sustained response was 23% vs 0%, respectively.

Although OS data remain immature, an interim OS analysis found a positive trend favoring talazoparib with a 24% reduction in the risk of death. The median OS was 22.3 months (95% CI, 18.1-26.2) with the PARP inhibitor compared with 19.5 months (95% CI, 16.3-22.4) with chemotherapy (HR, 0.76; 95% CI, 0.54-1.06; P = .105).

Regarding safety, the most common grade 3 adverse events (AEs) in the talazoparib arm were anemia (38% versus 4% in the chemotherapy arm), neutropenia (18% versus 20%, respectively), and thrombocytopenia (11% versus 2%, respectively). The safety population included 286 patients in the talazoparib arm and 126 patients in the chemotherapy arm.

Grade 4 AEs occurring most often with talazoparib included anemia (1%), neutropenia (3%), and thrombocytopenia (4%). Discontinuation of treatment due to AEs occurred in 5% and 6% of the talazoparib and chemotherapy arms, respectively.

“In the EMBRACA trial, Talzenna reduced the risk of disease progression by 46% and more than doubled the overall response rate compared to chemotherapy,” Johannes Ettl, MD, Department of Obstetrics and Gynecology, Klinikum rechts der Isar, Technical University of Munich in Germany and an investigator in the EMBRACA trial, said in the press release. “This improvement in outcomes for patients treated with Talzenna reinforces the increasingly key role of genetic testing in treatment decision-making for patients with locally advanced or metastatic breast cancer.”

The FDA approved talazoparib in this setting in October 2018, also based on the EMBRACA trial findings.

References

1. European Commission Approves TALZENNA® (talazoparib) for Patients with Inherited (Germline) BRCA-Mutated Locally Advanced or Metastatic Breast Cancer. Pfizer. Published June 21, 2019. https://bit.ly/31Qdpjw. Accessed June 21, 2019.
2. Litton JK, Rugo HS, Ettl J, et al. A phase 3 trial comparing talazoparib, an oral PARP inhibitor, to physician’s choice of therapy in patients with advanced breast cancer and a germline BRCA-mutation. Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS6-07.